The human immunodeficiency virus HIV is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease characterized by the destruction of the immune system, particularly of the CD4+ T-cell, with attendant susceptibility to opportunistic infections. HIV infection is also associated with a precursor AIDs-related complex (ARC), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
In common with other retroviruses, the HIV genome encodes protein precursors known as gag and gag-pol which are processed by the viral protease to afford the protease, reverse transcriptase (RT), endonuclease/integrase and mature structural proteins of the virus core. Interruption of this processing prevents the production of normally infectious virus. Considerable efforts have been directed towards the control of HIV by inhibition of virally encoded enzymes.
Currently available chemotherapy targets two crucial viral enzymes: HIV protease and HIV reverse transcriptase. (J. S. G. Montaner et al. Antiretroviral therapy: ‘the state of the art”, Biomed & Pharmacother. 1999 53:63-72; R. W. Shafer and D. A. Vuitton, Highly active retroviral therapy (HAART) for the treatment of infection with human immunodeficiency virus type I, Biomed. & Pharmacother. 1999 53:73-86; E. De Clercq, New Developments in Anti-HIV Chemotherap. Curr. Med. Chem. 2001 8:1543-1572) Two general classes of RTI inhibitors have been identified: nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI).
NRTIs typically are 2′,3′-dideoxynucleoside (ddN) analogs which must be phosphorylated prior to interacting with viral RT. The corresponding triphosphates function as competitive inhibitors or alternative substrates for viral RT. After incorporation into nucleic acids the nucleoside analogs terminate the chain elongation process. HIV reverse transcriptase has DNA editing capabilities which enable resistant strains to overcome the blockade by cleaving the nucleoside analog and continuing the elongation. Currently clinically used NRTIs include zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC) and tenofovir (PMPA).
NNRTIs were first discovered in 1989. NNRTI are allosteric inhibitors which bind reversibly at a nonsubstrate-binding site on the HIV reverse transcriptase thereby altering the shape of the active site or blocking polymerase activity. (R. W. Buckheit, Jr., Non-nucleoside reverse transcriptase inhibitors: perspectives for novel therapeutic compounds and strategies for treatment of HIV infection, Expert Opin. Investig. Drugs 2001 10(8)1423-1442; E. De Clercq The role of non0-nuceloside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection, Antiviral Res. 1998 38:153-179; G. Moyle, The Emerging Roles of Non-Nucleoside Reverse Transcriptase Inhibitors in Antiviral Therapy, Drugs 2001 61(1):19-26) Although over thirty structural classes of NNRTIs have been identified in the laboratory, only three compounds have been approved for HIV therapy: efavirenz, nevirapine and delavirdine. Although initially viewed as a promising class of compounds, in vitro and in vivo studies quickly revealed the NNRTIs presented a low barrier to the emergence of drug resistant HIV strains and class-specific toxicity. Drug resistance frequently develops with only a single point mutation in the RT.
While combination therapy with NRTIs, PIs and NNRTIs has, in many cases, dramatically lowered viral loads and slowed disease progression, significant therapeutic problems remain. The cocktails are not effective in all patients, potentially severe adverse reactions often occur and the rapidly reproducing HIV virus has proven adroit at creating mutant drug-resistant variants of wild type protease and reverse transcriptase. There remains a need for safer drugs with activity against wild type and commonly occurring resistant strains of HIV.
In WO9804135 published Feb. 5, 1998, J. L. Romain et al. disclose heterocyclic compounds of formula 1 which are potassium channel modulators. Heterocyclic groups disclosed
include, inter al., 1a and 1b where Z is O or S, Z1 is O, S or NR and m and n are 0 or 1.
In WO2002038553 published May 16, 2002, M. B. Mantlo et al. disclose triazolone compounds of formula 2 which are peroxisome proliferators Activated Receptor alpha (PPARα) agonists.

Compounds are disclosed in the invention where X is (CH2)1-5 wherein a carbon atom can optionally be replaced with O, S or NH; R1 and R2 are independently hydrogen, C1-8 alkyl, aryl-C0-4 alkyl, heteroaryl-C0-4 alkyl, C3-6 cycloalkyl-C0-2 alkyl or CH2COR17R18, Y is O, S, NH, C or a single bond and W is O or S.
In EP 0-435177 published Jul. 3, 1991, John M. Kane and Francis P. Miller disclose triazolones
of formula 3 where R1 is hydrogen or C1-4 alkyl. Compounds are disclosed to exhibit anticonvulsant activity.
In WO9613264 published May 9, 1996, S. J. Dominianni et al. disclose heterocycles according to
formula 4 and related compounds where Z1 is O, S, or NR exhibit oral hypoglycemic activity.
In U.S. Pat. No. 5,436,252 published Jul. 25, 1995, S. M. Sorenson et al. disclose 5-aryl-3H-1,2,4-triazol-3-ones according to formula 5 wherein R1 is hydrogen or R2, R2 is lower alkyl and R is individually hydrogen, alkyl, alkoxy, hydroxyl, halogen and trifluoromethyl. The disclosed compounds are useful for the treatment of neurodegenerative diseases.

In U.S. Pat. No. 5,331,002 published Jul. 19, 1994, J. A. Miller discloses 5-(optionally substituted)phenyl-4-alkyl-3H-1,2,4-triazole-3-thiones according to formula 105 useful in the enhancement of memory and cognition and treatment of Alzheimer's disease.

H. Yüksek et al. disclose the antibacterial activities of some of triazolones in Synthesis and Antibacterial Activities of some 4,5-Dihydro-1H-1,2,4-triazol-5-ones in Arzneim. Forschung. 1997 47(4):405-409.
Herbicidal and pesticidal properties of triazolones, oxadiazolones and thiadiazolones have been reported. K.-H. Linker et al. disclose pesticidal properties of triazolones in WO 9641535. F. Gozzo et al. disclose insecticidal, nematocidal and acaricidal properties of phosphonic acid esters of triazolones in U.S. Pat. No. 4,400,517 and U.S. Pat. No. 4,220,789. T. Kimata et al. disclose insecticide properties of 1-carbamoyltriazolones in U.S. Pat. No. 5,155,124 and U.S. Pat. No. 5,208,231. K. H. Mueller et al. disclose herbicidal properties of sulfonylaminocarbonyltriazolinones in U.S. Pat. No. 5,532,378 and U.S. Pat. No. 5,625,074. F. Bettarini et al. disclose miticidal and insecticidal activity of (thia)oxadiazol- and triazol(thi)ones in EP 533206. F. Bettarini et al. disclose the synthesis and acaricidal activity of 3-aryl-5-arylmethyl-1,3,4-oxa(thia)diazol-2(3H)-ones in Pesticide Science 1994 40(2):141-6. These compounds are not in the scope of the present disclosure.
U.S. Ser. No. 10/807,766 (U.S. Patent Publication 20040192704) filed Mar. 23, 2004 discloses benzyl-triazolone and benzyl-oxa(thia)diazolone compounds which inhibit HIV reverse transcriptase (HIV RT) U.S. Ser. No. 10/807,993 filed Mar. 23, 2004 (U.S. Patent Publication 20040198736) discloses benzyl-pyridazinone compounds which inhibit HIV RT. A U.S. application filed Apr. 22, 2005 by J. P. Dunn et al. claiming priority to U.S. Ser. No. 60/565,117 filed Apr. 23, 2004 discloses N-aryl 3-phenoxy-phenylacetamide compounds what are inhibitors of HIV reverse transcriptase. These applications are herein incorporated by reference in their entirety. In U.S. Ser. No. 11/085,869 filed Mar. 22, 2005 J. P. Dunn et al. disclose prodrugs of benzyl-pyridazinone compounds, including N-acyloxymethyl derivatives.
Drug failure can result in selection pressure for resistant strains. The facility which mutations occur during HIV replication has resulted in a large number of strains in the infected population. This has resulted in the need for drugs that exhibit activity against a spectrum of reverse transcriptase with one or more point mutations. Since the efficacy generally varies against different mutants, high circulating levels of the active pharmaceutical ingredient must be available to provide adequate activity against even the most resistant strain and avoid selection pressure which would favor resistant strains. The triazolones (I, R4═H) previously disclosed lack sufficient bioavailability to produce adequate blood levels to control all the commonly observed strains.
Chemical derivatization of active drug moieties is frequently undertaken for a variety of reasons including modification of undesirable physical properties of the active drug, optimization of the pharmacokinetic parameters effected absorption, distribution and metabolism of the active ingredient and site-specific targeting or localization of the active moiety to specific target tissues or cells. Albert introduced the term prodrug to describe a compound which lacks intrinsic biological activity but which is capable of in vivo transformation to an active drug substance (A. Albert, Selective Toxicity, Chapman and Hall, London, 1951). While the metabolic transformation can catalyzed by specific enzymes, often hydrolases, the active compound can also be released by non-specific chemical processes. Prodrugs have been recently reviewed (P. Ettmayer et al., J. Med. Chem. 2004 47(10):2393-2404; K. Beaumont et al., Curr. Drug Metab. 2003 4:461-485; H. Bundgaard, Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities in Design of Prodrugs, H. Bundgaard (ed) Elsevier Science Publishers, Amsterdam 1985; G. M. Pauletti et al. Adv. Drug Deliv. Rev. 1997 27:235-256; K. Beaumont et al. Curr. Drug Metab. 2003 4:461-485).
Amide (7) prodrugs have included N-hydroxymethyl derivatives (8a) the most common of which are N-acyloxymethyl (8b) compounds. (H. Bundgaard supra, pp 10-27; S. A. Varia et al., J. Pharm. Sci., 1984 73(8):1068-1073).

Potential prodrug candidates can sometimes be identified based on the chemical functionality contained in the molecule. However, chemical modifications which alter one aspect of the physical, chemical and biological properties of a molecule may introduce other undesirable properties not observed in the parent molecule. Thus, the identification of prodrugs is an uncertain and challenging exercise.